The ontogeny of the human globin genes is an important focus of study both with respect to the fundamental developmental biology and molecular genetics of the control of expression of this complex gene system, but also because modifying this developmental control would be of therapeutic value in the treatment of the prevalent genetic diseases of hemoglobin, such as sickle cell anemia and thalassemia. This has been one of our research emphases for more than 25 years. Among other findings was our demonstration that hydroxyurea, now approved to treat sickle cell anemia by elevating fetal hemoglobin, affects intracellular nitric oxide metabolism, specifically changing cyclic GMP levels. These results brought together our NO (see Annual Reports DK025093 and DK025104) and our sickle cell work and has led us to continue gene expression studies in human hematopoietic cells in collaborative studies. One such study shows that many transcription factors change during ontogeny of human CD34+ erythroid cells in culture, especially related to the JAK-STAT and AKT pathways. In more recent studies, just published, we showed that CD 34+ cells have increased levels of gene expression of the PI3/AKT and MAPK genes related to the mTOR signaling pathways as compared to other hematopoietic cells. We have recently reported that high levels of reticulocytosis in early infancy in children with sickle cell anemia is correlated with a subsequent more severe clinical course and have planned studies to see if this relates to adhesive properties of these reticulocytes. We have also helped analyze clinical data from the large number of sickle cell patients followed at NIH and showed that increases of fetal hemoglobin correlates well with apparent benefit-as measured by organ pathology or mortality-from hydroxyurea therapy. Our long interest in understanding the pain phenotype in these patients has resulted in analyses which suggest that there are both central and peripheral nervous system aspects to perception of pain.